Method for manufacture of 4-hydroxy pyran-2-one derivatives

ABSTRACT

A process for preparation of 4-hydroxy-pyran-2-one derivative of formula (I), 
                         
wherein R is,
 
                         
and wherein R 1  and R 2  are methyl and R 3  is hydrogen or methyl,
     comprising the steps of,   heating a compound of formula (II),   
                         
wherein R is as defined before, and R 4  is hydrogen, NH 4   +  or an alkali metal,
     in a solvent mixture consisting of an aromatic hydrocarbon and a ketone in an inert atmosphere at a temperature of between 60° C. to 92° C. in the absence or presence of orthophosphoric acid or its alkali dihydrogen salts or alkali hydrogen salts of a dibasic acid, followed by optional neutralization of the reaction mixture with an organic base and obtaining compound of formula (I) in high purity and substantially free of impurities through a step of isolation and crystallization. The process leads to formation of derivatives of formula I in high purity with dimmer impurity (III) less than 0.1% and anhydro impurity (IV) below 0.15%.

FIELD OF INVENTION

The present invention relates, to an improved method for manufacture of4-hydroxy-pyran-2-one derivative of formula (I) from the corresponding3,5-dihydroxy pentanoic acid derivative of formula (II) in high purity.

BACKGROUND OF THE INVENTION

HMG-CoA reductase inhibitors are valuable anti-hypercholesterolemicdrugs, which inhibit the biosynthesis of cholesterol by competitivelyinhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoAreductase) and leading to a reduction in the rate of formation ofcholesterol in the human body.

Therapeutically and commercially valuable anti-hypercholestoremic drugsinclude atorvastatin, lovastatin, mevastatin, pravastatin, simvastatin,rosuvastatin, fluvastatin etc. which can be represented by the generalstructural formula (I), wherein,

While, some of these drugs like lovastatin, simvastatin and mevastatinhave a 4-hydroxy pyran-2-one structure in the cyclised lactone form, inothers the 4-hydroxy pyran-2-one substituent is present in the openchain form i.e. as 3,5-dihydroxy pentanoic acid derivative (II).

Invariably, there is a common step of lactonisation in all the statincompounds, involving lactonisation of the corresponding 3,5-dihydroxypentanoic acid derivative (II) to the 4-hydroxy pyran-2-one derivativeof formula (I).

For example, lovastatin (Ia) is prepared by lactonisation of the3,5-dihydroxy pentanoic acid derivative (II) to (Ia) either by heatingin an organic solvent or in the presence of an acid catalyst. Theformer, viz. mevinolinic acid, is obtained from a fermentation brothcontaining Asperigillus Terreus.

Similarly, simvastatin (Ib), a structural analogue of lovastatin, havingan additional methyl group in the 2-methyl butyryl substituent issynthesized from lovastatin.

The final step in the synthesis of lovastatin or simvastatin involveslactonisation of the intermediate 3,5-dihydroxy acid derivative or itssalt either in the presence or absence of an acid catalyst as disclosedin the following documents:

-   -   i) U.S. Pat. No. 4,231,938 discloses a method for preparation of        lovastatin by lactonisation of mevinolinic acid in refluxing        ethyl acetate and in presence of a strong acid like hydrochloric        acid.    -   ii) U.S. Pat. No. 4,444,784 discloses a method for lactonisation        of the 3,5-dihydroxy pentanoic acid derivative by heating the        reaction mixture with a dilute acid to give simvastatin (I).        There is however no enabling disclosure about how the        transformation is brought about and also there is no mention        about the level of impurities formed during the lactonisation of        the hydroxy acid.    -   iii) EP 0 877 742 teaches a method for lactonisation of        mevinolinic acid present in a pre-treated fermentation broth by        heating in a chlorinated solvent at pH 2.5-4.0 in the presence        of a hydrochloric acid.    -   iv) U.S. Pat. No. 5,712,130 describes a method for lactonisation        of mevinolinic acid by heating a acidified fermentation broth in        butyl acetate at 40° C. to give lovastatin having purity of 90%.    -   v) U.S. Pat. No. 4,820,850 discloses a lactonisation method        comprising of heating the simvastatin ammonium salt (II) in a        hydrocarbon solvent such as toluene for 2-12 hours at 100° C.,        in the absence of an acid without disclosing the yield and        purity.    -   vi) U.S. Pat. No. 4,916,239 claims and discloses a method for        lactonisation of simvastatin ammonium salt comprising of        agitating the ammonium salt (II) in a mixture of a        water-miscible solvent, water and a acid catalyst at 20-30° C.    -   vii) U.S. Pat. No. 5,939,564 claims and discloses a method for        lactonisation of the open ring 3,5-dihydroxy pentanoic acid        derivative in the presence of a catalyst such as a salt of an        organic base with an organic acid or inorganic acid like        pyridine hydrobromide, pyridine hydrochloride or pyridine        p-toluene sulfonate salt in a lower alkanol, ketone, ether,        nitrile or mixture thereof (20-30 times dilution) at a        temperature between ambient and 50° C.    -   viii) U.S. Pat. No. 5,917,058 A1 claims and discloses a method        for preparation of simvastatin comprising lactonisation of the        3,5-dihydroxy pentanoic acid derivative in a weak acid such as        acetic acid and in absence of a strong acid at a temperature        below 55° C., and isolating simvastatin by addition of an        anti-solvent such as water, hexane, heptane or cyclohexane.    -   ix) U.S. Pat. No. 6,562,984 describes a method for lactonisation        in a solvent such as dichloromethane or acetonitrile and        reagents such as methanesulfonic acid, phosphorous pentoxide,        acidic ion exchange resin, molecular sieves, acidic clay, acidic        silica gel and combinations thereof which binds water produced        in a insoluble complex at a temperature not greater than 50° C.,        and preferably between 10-40° C.    -   x) U.S. Pat. No. 6,649,775 claims and discloses a process for        lactonisation of 3,5-dihydroxy acid by refluxing in a inert        organic solvent such as toluene and in the presence of large        quantities (2 moles) of dehydrating agents like magnesium        sulphate, sodium sulphate, calcium chloride, and molecular        sieves for removal of water and shifting of equilibrium towards        formation of the product.    -   xi) WO 02/094803 A1 claims and discloses a method for        lactonisation of 3,5-dihydroxy pentanoic acid derivative or its        ammonium salt in a mixture of acetonitrile and glacial acetic        acid in anhydrous conditions at 65-70° C. and in the absence of        a catalyst.    -   xii) WO 02/094804 A1 claims and discloses a method for        lactonisation of simvastatin intermediate (II) comprising of        heating in xylene at 135-140° C. for 20-30 minutes. The reaction        is carried out in a very high dilution of 25-50 times and the        dimer impurity (III) is formed in the range of 0.10 to 0.20%        without any disclosure about the formation of other impurities.    -   xii) WO 02/00615 A2 describes a method for lactonisation of        lovastatin by heating the broth with a mineral acid at 50-60°        C., followed by extraction with a hydrophobic solvent such as        toluene. Lactonisation is very slow requiring 20-60 hours and        also the yield is quite low (54%).    -   xiii) US Application No. 2003/0109723 A1 discloses and claims a        method for lactonisation of 3,5-dihydroxy pentanoic acid        derivative or its ammonium salt comprising of refluxing the said        hydroxy acid in a mixed organic solvent selected from toluene,        ethyl acetate, isopropyl acetate, dichloromethane, chloroform,        tetrahydrofuran and acetone, without an acid catalyst and under        nitrogen sweep.        -   Lactonisation is carried out in a high dilution (40-50            times) of the solvent mixture.

Further, anti-hypercholestoremic drugs, such as atorvastatin,rosuvastatin and fluvastatin, which are prepared by the synthetic routealso involve lactonisation of the 3,5-dihydroxy pentanoic acidderivative to give the corresponding 4-hydroxy pyran-2-one derivative,which is an intermediate of the above statin drugs.

U.S. Pat. No. 4,346,227 discloses a method for preparation of apravastatin intermediate by cyclisation of the 3,5 dihydroxy acid inpresence of a strong acid such as trifluoroacetic acid. This patent doesnot provide any enabling disclosure for the same.

U.S. Pat. No. 5,273,995 discloses a method for lactonisation of asubstituted 3,5 dihydroxy atorvastatin derivative by refluxing intoluene in the presence of a strong acid like hydrochloric acid.

U.S. Pat. No. 4,739,073 discloses a method for lactonisation of a3,5-dihydroxy derivative of fluvastatin wherein the reaction is carriedout in the absence of an acid by refluxing in benzene.

From the above, it would be evident that all the methods disclosed inthe prior art for synthesis of 4-hydroxy pyran-2-on derivatives (I)either involve heating 3,5-dihydroxy pentanoic acid derivative (II) in aorganic solvent in presence or absence of an acid or carrying out thereaction at lower temperature in the presence of a strong acid such asmethanesulfonic acid or in solvents such as acetic acid.

Lactonisation of the 3,5-dihydroxy pentanoic acid derivative or its salt(II) is invariably accompanied by the formation of associated impuritiesespecially the dimer impurity (III), in variable amounts and which isdifficult to remove utilizing conventional methods of purification andif removed, considerably lowers the yield of the product. The dimerimpurity (III) is formed by reaction of the 3-hydroxy group of onemolecule of compound (II) with the carboxyl group of another molecule ofcompound (II).

In summary, the prior art methods suffer from the followingshortcomings:

-   -   i. These methods do not mention the level of impurities formed        during lactonisation and also the yields obtained are generally        low, thereby rendering these methods costly for commercial        applications.    -   ii. Although, some of the methods, mention that the level of        dimer impurity (III) is reduced below 0.1%, but there is        absolutely no mention about other impurities such as        anhydro (IV) and acetyl impurity (V), which could be formed when        strong acids like methanesulfonic acid or a solvent like glacial        acetic acid is employed.

-   -   -   Compounds having the above impurities are difficult to            purify, by conventional methods of purification and            therefore, should be minimized at the reaction stage itself.

    -   iii. The level of dilution utilized by the prior art methods is        also very high viz. between 40-50 times (w/w) per gram of the        starting compound, thus reducing the production capacity and        increasing the time cycle for each run.

    -   iv. Some of the methods require a long time between 20-60 hours        for lactonisation, thereby reducing the production capacity        commercially.

As the anti-hypercholestoremic drugs of formula (I) are valuablecommercially and therapeutically, therefore, a need exists to synthesizethese drugs having a 4-hydroxy pyran-2-one substituent in theirstructural formula by a method which not only reduces the level ofimpurities but also reduces reaction time, solvent dilution and givescompound (I) of high purity, substantially free from impurities.

The present inventors have found that 4-hydroxy pyran-2-one derivative(I) can be synthesized in a higher yield and purity through a highlyselective method, comprising heating of 3,5-dihydroxy pentanoic acidderivative of formula (II) in a mixture of a aromatic hydrocarbon and aketonic solvent at a temperature in the range of 60-92° C., which givesthe object compound (I),

-   -   a) in higher yield (63-78%).    -   b) of high purity above 99.5%.    -   c) substantially free from the dimer impurity (III) and other        associated impurities such as the anhydro impurity (IV). There        is no possibility of forming the acetyl impurity (V), since the        present method does not utilize acetic acid or its derivatives.    -   d) in shorter reaction time of between 2.0 to 12.0 hours.

Further, it has been found that the reaction could be carried out usingalmost half the dilution of the solvent utilized in prior art methods.Significantly, the reaction could be carried out in the absence orpresence of a weak acid like orthophosphoric acid. Both the conditionswere found not to have any significant effect on the quality, formationof impurities etc.

Even though, various aromatic hydrocarbons and ketones could be used forconversion of compound (II) to (I), however the most optimum resultswere obtained when toluene and methyl ethyl ketone were used.

OBJECTS OF THE INVENTION

An object of the invention is to provide an improved process forpreparation of 4-hydroxy pyran-2-one derivative of formula (I) of highpurity, with dimer impurity of formula (III) less than 0.1% and anhydroimpurity of formula (IV) less than 0.15%.

Another object of the invention is to provide a improved process forsynthesis of 4-hydroxy pyran-2-one derivative of formula (I) by heatingthe corresponding 3,5-dihydroxy pentanoic acid derivative or its salt offormula (II) in a mixture of a aromatic hydrocarbon and a ketone and inpresence or absence of a weak acid like orthophosphoric acid or itsalkali dihydrogen salt or alkali hydrogen salt of dibasic acid and at atemperature between 60-92° C. and in a in a short duration of 2.0 to12.0 hours as compared to between 20-60 hours reported in prior artmethods.

Yet, another object of the invention relates to carrying out thelactonisation of the compound of formula (II) in a significantly lowerdilution of the solvent mixture between 13 to 17 times (w/w) per gram ofcompound (II) giving compound (I) of high purity and thereby making theprocess cost-effective.

SUMMARY OF THE INVENTION

According to the main aspect of the present invention there is provideda process for preparation of a compound of formula (I),

wherein R is,

and wherein R¹ and R² are methyl and R³ is hydrogen or methyl,comprising the steps of,heating a compound of formula (II),

wherein R is as defined before, and R⁴ is hydrogen, NH₄ ⁺ or an alkalimetal,in a solvent mixture consisting of an aromatic hydrocarbon and a ketonein an inert atmosphere at a temperature of between 60° C. to 92° C. inthe absence or presence of orthophosphoric acid or its alkali dihydrogensalts or alkali hydrogen salts of a dibasic acid, followed by optionalneutralization of the reaction mixture with an organic base andobtaining compound of formula (I) in high purity and substantially freeof impurities through a step of isolation and crystallization.

DETAILED DESCRIPTION OF THE INVENTION

The present inventors have found that 4-hydroxy pyran-2-one derivative(I) can be synthesized from the 3,5-dihydroxy pentanoic acid derivativeor its salt (II) by heating in a mixture of an aromatic hydrocarbon anda ketone in a period of 2.0-12.0 hours, optionally in the presence of aweak acid like orthophosphoric acid or its alkali dihydrogen salt or aalkali hydrogen salt of a dibasic acid to give compound (I), of highpurity, with dimer impurity (III) below 0.1% and anhydro impurity (IV)below 0.15%, and which conforms to pharmacopoeial specification.

One aspect of the present invention provides a simple, efficient, costeffective method for manufacture of 4-hydroxy pyran-2-one derivatives offormula (I) of high purity substantially free from impurities.

Another aspect of the invention provides a method for manufacture of4-hydroxy pyran-2-one derivatives of formula (I) by heating thecorresponding 3,5-dihydroxy pentanoic acid derivative or its salt offormula (II) in a mixture of an aromatic hydrocarbon and a ketone in aratio of 7:3.

Yet another aspect of the invention provides a method for manufacture of4-hydroxy pyran-2-one derivatives of formula (I) by heating thecorresponding 3,5-dihydroxy pentanoic acid derivative or its salt offormula (II) in a mixture of a toluene and methyl ethyl ketone.

A further aspect of the invention relates to a method comprising ofheating the compound (II) or its salt in the presence or absence of aweak acid like orthophosphoric acid or its alkali dihydrogen salt oralkali hydrogen salt of a dibasic acid.

Yet a further aspect of the invention relates to a method for carryingout the lactonisation in a very low dilution between 13 to 17 times ofthe solvent mixture, at a temperature of 60-92° C., in a short time of2.0 to 12.0 hours followed by evaporation of the solvent mixture andisolating the product of formula (I) from a hydrophobic solvent.

Yet another aspect of the invention relates to a method for purificationof compound (I) by refluxing in a hydrophobic solvent and filtering thecooled mixture, followed by recrystallisation of compound (I) from amixture of a water-miscible solvent and water to give compound (I) ofhigh purity, having dimer impurity less than 0.1%, anhydro impurity lessthan 0.15 and conforming to pharmacopoeial specifications.

The selection of the solvent combination, ratio of the solvent mixture,dilution of the solvents, reaction temperature, and the absence orpresence of a weak acid such as orthophosphoric acid or its alkalidihydrogen salts in providing 4-hydroxy-pyran-2-one derivatives offormula (I) of high purity with dimer impurity (III) less than 0.1% andanhydro impurity (IV) below 0.15%, forms the basis of the invention.

The method of manufacture of 4-hydroxy pyran-2-one (I) as per thepresent invention is summarized in Scheme-I for ready reference.

All the lactonisation experiments illustrated hereafter are all carriedout on the corresponding 3,5-dihydroxy pentanoic acid derivative or saltof simvastatin (II).

A. Lactonisation of 3,5-Dihydroxy Pentanoic Acid Derivatives of Formula(I).

The lactonisation of 3,5-dihydroxy pentanoic acid derivative of formula(II) to give 4-hydroxy pyran-2-one derivative of formula (I) was foundto depend on the following parameters:

-   -   i) selection of the solvent mixture and their ratio,    -   ii) dilution of the solvent,    -   iii) reaction temperature,    -   iv) selection of proton donors for promoting lactonisation.        i) Selection of the Solvent Mixture and Their Ratios.

Several solvents selected from aromatic hydrocarbons, ketones, andaliphatic hydrocarbons as mixtures were tried out in equal proportionsto find out the solvent medium, which would minimise impurities such asdimer (III) and anhydro (IV) and give higher conversion of the product(I).

Aromatic hydrocarbons were selected from benzene, toluene, xylene butpreferably toluene; ketones were selected from acetone, methyl ethylketone, methyl isobutyl ketone, and aliphatic hydrocarbons were selectedfrom hexane, and cyclohexane but preferably cyclohexane.

The results obtained utilizing the above solvents in equal proportionare summarized in Table-I.

TABLE I Comparison of various solvent mixtures in terms of conversion,impurity formation at reflux temperature in a solvent dilution of 17times (w/w) per gram of the starting material Level of impurities(1:1)(w/w) Ratio Reaction Product in reaction (%) of various TimeConversion Dimer Anhydro No. solvent mixtures (hrs) (%) (III) (IV) 1.Toluene/acetone 46.0 91.95 0.65 0.41 2. Toluene/methyl 35.0 93.0 0.260.41 ethyl ketone 3. Methyl isobutyl 18.0 94.84 0.14 0.86 ketone/methylethyl ketone 4. Cyclohexane/ 9.0 86.5 0.6 0.8 methyl ethyl ketone

It is evident from the above data that among all these combinations,toluene/methyl ketone was found to be better than the others, as

-   -   i) it had a lower impurity formation, although the reaction time        was higher than the other combinations except toluene/acetone.    -   ii) methyl ethyl ketone has a lower boiling point than the other        solvents therefore, evaporation of the solvent is easier during        isolation of the product as compared to other solvents.

Based on the result shown in Table-I, the inventors tried to see whethera change in the weight ratio of the solvent mixture from (1:1) ratio oftoluene and methyl ethyl ketone would have any effect on the conversionof product (I) and impurity profile of the reaction. It was indeed foundthat changing the ratio of the toluene/methyl ethyl ketone mixture from(1:1) to (7:3) greatly increased the reaction rate, with reactioncompleting in only 12 hours which is much faster than (1:1) ratio,thereby considerably reducing the time for each run.

The results are summarized in Table-II, which shows the effect ofdifferent weight ratios of toluene/methyl ethyl ketone on reaction rate,conversion of 4-hydroxy pyran-2-one, and formation of impurities.

TABLE II Comparison of results obtained with different ratios oftoluene/methyl ethyl ketone solvent mixture (in absence of acid) atreflux temperature Level of Ratio of impurities during Level ofimpurities in the toluene/ Product reaction (%) isolated product (I)methyl ethyl Reaction conversion Dimer Anhydro Product purity betweenNo. ketone. time(hrs) (%) (III) (IV) 99-100%. 1. 1:1 35.0 93.00 0.260.41 Individual impurities less 2. 3:1 6.0 94.85 0.46 0.60 than 0.15%and dimer 3. 7:3 12.0 92.85 0.20 0.41 impurity less than 0.1% 4. 3:745.0 89.63 0.68 0.78

Lactonisation utilising the (7:3) combination of toluene and methylethyl ketone was extrapolated to other ketones to observe the effect onconversion, formation of impurities and reaction time.

The results obtained in the study are summarized in Table-III

TABLE III Lactonisation of 4-hydroxy-pyran-2-ones utilising variouscombinations of toluene with ketones (absence of orthophosphoric acid orits dihydrogen salt) in a weight 7:3 ratio at reflux temperature. Purityand level of Ketone utilised in Impurities impurities in the combinationwith Reaction Conversion Dimer Anhydro product (I). No. tolueneTime(hrs) (%) (%) (%) Purity between 99-100%. 1. Methyl ethyl 12.0 92.850.20 0.41 Individual impurities ketone below 0.15% and 2. Methylisobutyl 4.0 93.7 0.35 0.56 dimer impurity (III) ketone less than 0.1%.3. Cyclohexanone 6.5 93.82 0.29 0.46

Methyl ethyl ketone was found to be a better co-solvent as compared tothe other ketones since impurity formation was comparatively lower, andalso since it has a lower boiling point as compared to methyl isobutylketone and cyclohexanone, therefore evaporation of methyl ethyl ketoneis much easier during isolation of the product.

ii) Dilution of the Toluene/Methyl Ethyl Ketone Mixture Per Gram of the3,5-Dihydroxy Pentanoic Acid Derivative or its Ammonium Salt(II).

It is known from prior art methods that solvent dilution plays a majorrole in the formation of the dimer impurity (III). Methods reported inthe prior art reveal that the dimer impurity (III) is usually formedwhen the dilution of the solvent medium is low. Large solvent dilutionreduces the formation of dimer impurity (III) while lower dilutionincreases the formation of the dimer impurity (III). Reported methodspoint out to the utilisation of a very high dilution between 40-50 timesof the solvent as reaction medium for minimizing dimer impurity (III).

The present inventors have surprisingly found that with the presentmethod, dimer impurity (III) can be controlled even with a low dilutionof the solvent mixture. Dilution of toluene/methyl ketone between 13.0and 17.0 (w/w) per gram of the 3,5-dihydroxy pentanoic acid derivativewas found to be optimum in minimizing the dimer impurity (III) alongwith associated impurities and which is summarized in Table-IV.

TABLE IV Effect of solvent dilution on the conversion, formation ofimpurities, and reaction time during lactonisation of the3,5-dihydroxypentanoic acid derivative (II) in toluene/methyl ethylketone (7:3)weight ratio and temperature of 80 ± 5° C. Dilution of (7:3)toluene/ methyl ethyl Conversion ketone (w/w) of 4- per gram of Reactionhydroxy Impurities (%) the starting Time pyran-2- Dimer Anhydro No.material (hrs) one (%) (III) (IV) 1. 25.0 13.0 92.41 0.21 0.40 2. 17.012.0 92.85 0.20 0.41 3. 13.0 14.0 92.30 0.27 0.38 4. 4.0 5.5 92.24 1.231.48

It can be seen from the above data, that formation of the dimer impurity(III) is higher with a lower dilution of 4 times (w/w) per gram of thestarting material and impurity formation was minimized for a dilution of13.0 to 25.0 times of the solvent mixture (w/w) per gram of the startingcompound.

Thus a dilution of between 13.0 and 17.0 times was found to be optimumfor lactonisation which is in stark contrast to the high dilutionbetween 40-50 times employed by prior art methods. The utilization ofsuch low dilutions therefore makes the present method cost-effective.

iii) Reaction Temperature:

The inventors have studied the effect of temperature on lactonisationand found that at lower temperatures (below 50° C.) the reaction wasslow, while at higher temperatures (60-90° C.), the reaction was faster.The results of the experiments carried out different dilutions oftoluene/methyl ethyl ketone has been summarized in Table-V.

TABLE V Effect of temperature on the reaction time, conversion, impurityformation during lactonisation of 3,5-dihydroxy pentanoic acidderivative or its salts (II) [in presence of orthophosphoric acid] in17.0 times (w/w) dilution of the solvent. Impurity formation (%)Reaction Conversion Dimer Anhydro No. Temperature time (%) (III) (IV) 1.50° C. 4.5 hours 91.02 0.21 0.48 2. 65° C. 4.0 hours 92.12 0.20 0.45 3.70° C. 3.0 hours 93.28 0.28 0.50 4. 80° C. 2.0 hours 96.11 0.40 0.64 5.90° C. 0.5 hours 93.90 0.44 0.57

From the above table, it is evident that lactonisation can be carriedout at a temperature between 60-85° C., but preferably 80±2° C., whereinthe reaction is fast and the conversion is higher.

iv) Selection of Proton Donors for Promoting Lactonisation:

Several reagents such as orthophosphoric acid and its salts like sodiumdihydrogen phosphate, potassium dihydrogen phosphate, salts of dibasicacid like sodium hydrogen sulphate, potassium hydrogen sulphate,potassium hydrogen phthalate were tried out.

TABLE VI Effect of proton donors on the reaction time, conversion of4-hydroxy pyran-2-one(I), formation of impurities utilizingtoluene/methyl ethyl ketone (7:3)(w/w) mixture at a temperature of 80°C. Reac- Formation of tion Conver- impurities (%) Time sion DimerAnhydro No. Reagent (hrs) (%) (III) (IV) 1. Orthophosphoric acid 2.096.11 0.40 0.64 (88%) 2. Sodium dihydrogen 7.5 93.41 0.23 0.47 phosphate3. Potassium dihydrogen 13.0 92.44 0.50 0.56 phosphate 4. Potassiumhydrogen 12.0 89.86 0.33 0.57 sulphate 5. Potassium hydrogen 13.5 20.460.05 0.27 phthalate

It can be seen from Table-VI that from the above reagents,orthophosphoric acid was found to be a better proton donor, since theconversion was higher, impurity formation was lower, and most importantis the fact that the reaction was completed in a very short time of only2.0 hours.

The pH of the reaction medium is 3.5, when orthophosphoric acid is usedas compared to sodium dihydrogen phosphate (pH:4.5), potassiumdihydrogen phosphate (pH4.6), potassium hydrogen sulphate (pH1.5) andpotassium hydrogen phthalate (pH 4.5), which suggests that the processof lactonisation is fast at pH:3.5 as compared to other pH.

Lactonisation of 3,5-dihydroxy pentanoic acid derivative (II) was triedout in the presence of other ketones such as methyl isobutyl ketone,cyclohexanone and cyclopentanone. The results are summarized inTable-VII.

TABLE VII Lactonisation of 4-hydroxy-pyran-2-ones utilising variouscombinations of toluene with ketones (presence of orthophosphoric acid)in a (7:3) weight ratio and temperature of 80° C. Ketone utilised inImpurities (7:3)(w/w) Product (reaction mixture) combination withReaction conversion Dimer Anhydro No. toluene time(hrs) (%) (%) (%) 1.Methyl ethyl ketone 2.0 96.11 0.40 0.64 2. Methyl isobutyl 3.0 96.731.04 0.76 ketone 3. Cyclohexanone 3.0 91.28 0.24 0.94 4. Cyclopentanone4.0 88.65 1.15 0.63

The combination of toluene/methyl ketone was found to be superior tocombination of toluene with other ketones as the reaction is faster,conversion is higher and also the impurity formation is much lower ascompared to the other toluene combinations.

The reagents depicted in Table-VI, are employed in molar proportions ofbetween 0.95 to 1.10 moles per mole of the 3,5-dihydroxy pentanoic acidintermediate but preferably between 1.0 and 1.05 mole equivalent.

B. Isolation and Purification of 4-Hydroxy Pyran-2-One Derivatives ofFormula (I).

a. Isolation of Compound (I).

The reaction mixture is cooled to ambient temperature, quenched withwater and optionally neutralized with an organic base such as triethylamine.

The molar proportion of triethyl amine employed is between 1.0 to 1.10moles per mole of compound (I) but preferably between 1.01 and 1.05moles. The pH obtained is 7.5±0.2 after addition of triethyl amine [1.02moles per mole of compound (II)].

The aqueous layer is separated and the organic layer is concentratedunder reduced pressure to distil toluene/methyl ethyl ketone mixture.

A hydrophobic solvent preferably cyclohexane is added to the residue andthe mixture is again distilled under reduced pressure to completelystrip off toluene/methyl ethyl ketone mixture.

The amount of cyclohexane added is between 3.0 to 8.0 times weight pergram but preferably 5.0 times (w/w) of the compound (II).

Cyclohexane [5.0 times (w/w)] is again added to the syrupy residue andthe mixture agitated for 30 minutes at ambient temperature for completeprecipitation of compound (I). Compound (I) is filtered and purified assuch without drying.

b. Purification of Compound (I).

First Purification:

Wet cake of compound (I) obtained during isolation is added to ahydrophobic solvent preferably cyclohexane and refluxed for 15 minutes.The amount of cyclohexane added is between 15 and 25 times weight pergram of compound (II) but preferably 20 times (w/w) of compound (II).

The mixture is cooled to 10-15° C. and stirred for 120-150 minutes forcomplete crystallization of compound (I). The mixture is filtered andthe wet cake washed with cyclohexane.

Second Purification:

The wet cake obtained in the first purification is dissolved in awater-miscible solvent selected from alkanol and a ketone but preferablyan alkanol.

The alkanol is selected from methanol, ethanol, n-propanol, isopropanolbut preferably methanol.

Compound (I) is dissolved in methanol. The quantity of methanol added isbetween 8.0 to 12.0 times weight per gram of compound (II), butpreferably 10.0 times weight per gram of compound (II).

Butylated hydroxy toluene and butylated hydroxy anisole are added to themixture. The amount of the anti-oxidant added is 0.005% weight/weight ofcompound (II).

The mixture is optionally treated with activated carbon and filtered.Water is added gradually to the filtrate. The volume of water added isbetween 10.0 and 15.0 times volume by weight of compound (II), butpreferably 13.0 times volume/weight of compound (II). Water is added in30-45 minutes at ambient temperature and stirred at 60-90 minutes forcomplete crystallization of compound (I). The mixture is filtered andwashed with 25% aqueous methanol. The wet cake is dried at 40-45° C.under vacuum for 4.0 to 5.0 hours.

Compound (I) is obtained in a overall yield of between 63-70% forcompound (Ib) viz. simvastatin and between 75-80% for compound (Ia) viz.lovastatin.

The purity of the 4-hydroxy pyran-2-one derivatives thus obtained isbetween 99.5% and 99.8% with dimer impurity (III) below 0.1% and anhydroimpurity (IV) below 0.15%.

Lactonisation of 3,5-Dihydroxy Acid (II) in Presence of OrthophosphoricAcid:

In a specific embodiment, 3,5-dihydroxy pentanoic acid derivative (II)or its salt is added to a mixture of toluene [(12.0 parts w/w per partof compound (II)] and methyl ethyl ketone [5.0 parts w/w per part ofcompound (II)]. Nitrogen gas is bubbled into the reaction mixture,followed by addition of orthophosphoric acid [(1.05 mole equivalent perequivalent of compound (II)] at room temperature. The mixture isagitated at 80±2° C. for 2.0-2.5 hours with HPLC monitoring till thereaction proceeds to completion. The reaction mixture is cooled to25-30° C. and diluted with water (2.0 times v/v). Triethyl amine [1.0mole equivalent per mole of compound (II)] is added drop wise to themixture and agitated for 15 minutes. The aqueous layer is separated andthe organic layer is concentrated under reduced pressure. Cyclohexane [5times w/w per gram of the compound (II)] is added to the syrupy residueand the solvent evaporated to completely strip off toluene and methylethyl ketone. Cyclohexane [5 times w/w per gram of the compound (II)] isadded to the syrupy mass and the mixture agitated at 25-30° C. forcomplete crystallization of the lactone compound (I) containing4-hydroxy pyran-2-one ring. Compound (I) is filtered and washed withcyclohexane.

The wet cake is added to cyclohexane under a nitrogen atmosphere andrefluxed for 10-15 minutes. The mixture is allowed to cool between25-30° C., and agitated mildly for 1.0 hour. The mixture is furthercooled between 10-15° C. and stirred gently for 2.5 hours for completecrystallization of compound (I), which is then filtered and washed withcyclohexane.

The wet cake is then dissolved in methanol, to which butylated hydroxytoluene and butylated hydroxy anisole is added and after optional carbontreatment, the mixture is filtered and the carbon bed washed withmethanol. The filtrate is cooled to 25-30° C. and water is added slowlyto the filtrate for gradual crystallization of the pure compound (I),which is then filtered at 0-5° C. The wet cake is washed withmethanol:water (1:4) and dried at 40-45° C.

Lactonisation of 3,5-Dihydroxy Acid (II) in Absence of Acid.

In a specific embodiment, 3,5-dihydroxy pentanoic acid derivative (II)or its salt is added to a mixture of toluene [(12.0 parts w/w per partof compound (II)] and methyl ethyl ketone [5.0 parts w/w per part ofcompound (II)]. Nitrogen gas is bubbled into the reaction mixture, andthe mixture is agitated at 90±2° C. for 12.0-12.5 hours with HPLCmonitoring till the reaction proceeds to completion. The reactionmixture is cooled to 25-30° C. and the solvent mixture is evaporatedunder reduced pressure. Cyclohexane [5 times v/v per gram of thecompound (II)] is added to the syrupy residue and the solvent evaporatedto completely strip off toluene and methyl ethyl ketone. Cyclohexane [5times v/v per gram of the compound (II)] is added to the syrupy mass andthe mixture agitated at 25-30° C. for complete crystallization of thelactone compound (I) containing 4-hydroxy pyran-2-one ring. Compound (I)is filtered and washed with cyclohexane.

The wet cake is added to cyclohexane under a nitrogen atmosphere andrefluxed for 10-15 minutes. The mixture is allowed to cool between25-30° C., and agitated mildly for 1.0 hour. The mixture is furthercooled between 10-15° C. and stirred gently for 2.5 hours for completecrystallization of compound (I), which is then filtered and washed withcyclohexane.

The wet cake is dissolved in methanol, to which butylated hydroxytoluene and butylated hydroxy anisole is added and after optional carbontreatment, the mixture is filtered and the carbon bed is washed withmethanol. The filtrate is cooled to 25-30° C. and water is added slowlyto the filtrate for gradual crystallization of compound, which is thenfiltered at 0-5° C. The wet cake is washed with methanol:water (1:4) anddried at 40-45° C.

Compound (I) obtained by both the above methods (in presence of acid andabsence of acid) has purity between 99.6 and 100%, with dimer impurity(III) below 0.1% and anhydro impurity (IV) below 0.15%.

Compound (I) prepared by this method conforms to pharmacopoeialspecifications.

The invention is further illustrated by the following non-limitingexamples.

Example 1 Preparation of 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydro-1(S)-napthyl]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one(Simvastatin) {in Presence of Orthophosphoric Acid}

Ammonium-7-[1,2,6,7,8,8a(Rhexahydro-2(S),6(R)-dimethyl-8(S)-(2,2-dimethylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoate(Simvastatin ammonium salt) (100 gms; 0.22 moles) was added to a mixtureof toluene (1400 ml) and methyl ethyl ketone (600 ml). Nitrogen gas wasbubbled into the reaction mixture followed by drop wise addition oforthophosphoric acid (25.8 gms; 0.23 moles) at room temperature. Thereaction mixture was agitated at 80±2° C., for 2.0-2.5 hours with HPLCmonitoring. The reaction mixture was cooled to 20° C. and water (200 ml)followed by triethyl amine (22.29 gms; 0.22 moles) was added to themixture. The aqueous layer was separated and the organic layer wasdistilled under reduced pressure to completely remove the solventmixture. Cyclohexane (500 ml) was added and distilled again tocompletely strip off toluene/methyl ketone mixture. Cyclohexane (500 ml)was added to the syrupy mass and stirred for 30 minutes for completecrystallization of the product. The product was filtered and washed withcyclohexane (100 ml).

The wet cake was added to cyclohexane (2000 ml) and refluxed for 10-15minutes. The mixture was gradually cooled to 25-30° C. and stirred for3.0 hours. The mixture was cooled to 10-15° C. and filtered. The wetcake was washed with cyclohexane.

The wet cake obtained was dissolved in methanol (1000 ml). Butylatedhydroxy toluene (5 mgms) and butylated hydroxy anisole (5 mgms) wereadded to the mixture and after optional carbon treatment was filteredand cooled to 25-30° C. Water was added gradually to the filtrate in 45minutes and cooled to 0-5° C. The mixture was agitated at sametemperature for 90 minutes and filtered. The wet cake was washed with a(4:1) mixture of water:methanol (200 ml). The wet cake was dried at40-45° C. Yield: 62.56 gms; % Yield: 67.3; Purity: 99.7%.

Example-2 Preparation of6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydro-1(S)-napthyl]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one(Simvastatin) {in Absence of Orthophosphoric Acid}

Ammonium-7-[1,2,6,7,8,8a(R)-hexahydro-2(S),6(R)-dimethyl-8(S)-(2,2-dimethylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoate(Simvastatin ammonium salt) (100 gms; 0.22 moles) was added to a mixtureof toluene (1400 ml) and methyl ethyl ketone (600 ml). Nitrogen gas wasbubbled into the reaction mixture and the reaction mixture agitated at90±2° C., for 12.0-12.5 hours with HPLC monitoring. The reaction mixturewas cooled to 20° C. and distilled under reduced pressure to completelyremove the solvent mixture. Cyclohexane (500 ml) was added and distilledagain to completely strip off toluene/methyl ketone mixture. Cyclohexane(500 ml) was added to the syrupy mass and stirred for 30 minutes forcomplete crystallization of the product. The product was filtered andwashed with cyclohexane (100 ml).

The wet cake was added to cyclohexane (2000 ml) and refluxed for 10-15minutes. The mixture was gradually cooled to 25-30° C. and stirred for3.0 hours. The mixture was cooled to 10-15° C. and filtered. The wetcake was washed with cyclohexane.

The wet cake obtained was dissolved in methanol (1000 ml). Butylatedhydroxy toluene (5 mgms) and butylated hydroxy anisole (5 mgms) wasadded to the mixture and after optional carbon treatment was filtered,the carbon bed washed with methanol (200 ml) and cooled to 25-30° C.Water was added gradually to the filtrate in 45 minutes and cooled to0-5° C. The mixture was agitated at same temperature for 90 minutes andfiltered. The wet cake was washed with a (4:1) mixture of water:methanol(200 ml). The wet cake was dried at 40-45° C. Yield: 70.2 gms; % Yield:70%; Purity: 99.71%.

Example-3 Preparation of [1S-[1α(R*),3α,7β,8β(2S*,4S*),8a,β]]-2-methylbutanoic acid1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1-naphthalenylester (Lovastatin) {in Presence of Orthophosphoric Acid}

Ammonium-7-[1,2,6,7,8,8a(R-hexahydro-2(S),6(R)-dimethyl-8(S)-(2-methylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoate(lovastatin ammonium salt) (10 gms; 0.023 moles) was added to a mixtureof toluene (140 ml) and methyl ethyl ketone (60 ml). Nitrogen gas wasbubbled into the reaction mixture followed by drop wise addition oforthophosphoric acid (2.4 gms; 0.24 moles) at room temperature. Thereaction mixture was agitated at 80±2° C., for 2.0-2.5 hours with HPLCmonitoring. The reaction mixture was cooled to 20° C. and water (20 ml)followed by triethyl amine (2.3 gms; 0.023 moles) was added to themixture. The aqueous layer was separated and the organic layer wasdistilled under reduced pressure to completely evaporate the solventmixture. Cyclohexane (50 ml) was added and distilled again to completelystrip off toluene/methyl ketone mixture. Cyclohexane (50 ml) was addedto the syrupy mass and stirred for 30 minutes for completecrystallization of the product. The product was filtered and washed withcyclohexane (10 ml).

The wet cake was added to cyclohexane (200 ml) and refluxed for 10-15minutes. The mixture was gradually cooled to 25-30° C. and stirred for3.0 hours. The mixture was cooled to 10-15° C. and filtered. The wetcake was washed with cyclohexane.

The wet cake obtained was dissolved in methanol (1000 ml). Butylatedhydroxy toluene (0.5 mgms) and butylated hydroxy anisole (0.5 mgms) wasadded to the mixture and after optional carbon treatment was filteredand cooled to 25-30° C. Water was added gradually to the filtrate in 45minutes and cooled to 0-5° C. The mixture was agitated at sametemperature for 90 minutes and filtered. The wet cake was washed with a(4:1) mixture of water:methanol (200 ml). The wet cake was dried at40-45° C. Yield: 7.2 gms; % Yield: 78.2; Purity: 99.7%.

Example-4 Preparation of 6(R)-[2-[8(S)-(2,2-dimethylbutyryloxy)-2(S),6(R)-dimethyl-1,2,6,7,8,8a(R)-hexahydro-1(S)-napthyl]ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one(Simvastatin) {in Presence of Sodium Dihydrogen Phosphate}

Ammonium-7-[1,2,6,7,8,8a(R-hexahydro-2(S),6(R)-dimethyl-8(S)-(2,2-dimethylbutyryloxy)-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanoate(Simvastatin ammonium salt) (10 gms; 0.022 moles) was added to a mixtureof toluene (140 ml) and methyl ethyl ketone (60 ml). Nitrogen gas wasbubbled into the reaction mixture followed by addition of sodiumdihydrogen phosphate (25.8 gms; 0.23 moles) at room temperature. Thereaction mixture was agitated at 80±2° C., for 7.5-8.0 hours with HPLCmonitoring. The reaction mixture was cooled to 20° C. and water (200ml). The reaction mixture was distilled under reduced pressure tocompletely remove the solvent mixture. Cyclohexane (500 ml) was addedand distilled again to completely strip off toluene/methyl ketonemixture. Cyclohexane (500 ml) was added to the syrupy mass and stirredfor 30 minutes for complete crystallization of the product. The productwas filtered and washed with cyclohexane (100 ml).

The wet cake was added to cyclohexane (2000 ml) and refluxed for 10-15minutes. The mixture was gradually cooled to 25-30° C. and stirred for3.0 hours. The mixture was cooled to 10-15° C. and filtered. The wetcake was washed with cyclohexane.

The wet cake obtained was dissolved in methanol (100 ml). Butylatedhydroxy toluene (0.5 mgms) and butylated hydroxy anisole (0.5 mgms) wasadded to the mixture and after optional carbon treatment was filteredand cooled to 25-30° C. Water was added gradually to the filtrate in 45minutes and cooled to 0-5° C. The mixture was agitated at sametemperature for 90 minutes and filtered. The wet cake was washed with a(4:1) mixture of water:methanol (200 ml). The wet cake was dried at40-45° C. Yield: 6.3 gms; % Yield: 67.3%; Purity: 99.7%.

1. A process for preparation of a compound of formula (I),

wherein R¹ and R² are methyl and R³ is hydrogen or methyl, comprising the steps of, heating a compound of formula (II),

wherein R⁴ is hydrogen, NH₄ ⁺ or an alkali metal, in a solvent mixture consisting of toluene and methyl ethyl ketone in an inert atmosphere at a temperature between 60-85° C. and optionally in the presence of orthophosphoric acid or its alkali dihydrogen salts or alkali hydrogen salts of a dibasic acid, followed by optional neutralization of the reaction mixture with an organic base and obtaining compound of formula (I) in high purity and substantially free of impurities through a step of isolation and crystallization.
 2. A process according to claim 1, wherein the ratio of toluene and methyl ethyl ketone is between 8:2 and 2:8 (w/w).
 3. A process according to claim 1, wherein the proportion of the solvent mixture to the substrate is between 13 and 17 times (w/w) per gram of compound (II).
 4. A process according to claim 1, wherein orthophosphoric acid is employed in molar proportion of 1.0 mole to 1.2 moles per mole of compound (II).
 5. A process according to claim 1, wherein the alkali dihydrogen salts of orthophosphoric acid are selected from sodium dihydrogen phosphate and potassium dihydrogen phosphate.
 6. A process according to claim 1, wherein the molar proportion of alkali dihydrogen salt of orthophosphoric acid employed is 1.0 mole to 1.2 moles per mole of compound (II).
 7. A process according to claim 1 wherein the alkali hydrogen salts of the dibasic acid are selected from potassium hydrogen sulphate and sodium hydrogen sulphate.
 8. A process according to claim 7, wherein the molar proportion of the alkali hydrogen salt of the dibasic acid is 1.0 mole to 1.2 moles per mole of compound (II).
 9. A process according to claim 1, wherein the organic base is triethyl amine.
 10. A process according to claim 1, wherein the step of isolation comprises: i) evaporation of the solvent mixture, ii) addition of a hydrophobic solvent to the residue and evaporation of the solvent, iii) dissolution of the residue in a hydrophobic solvent, cooling to ambient temperature followed by collection of compound of formula (I) by filtration.
 11. A process according to claim 10, wherein the hydrophobic solvent is cyclohexane.
 12. A process according to claim 1, wherein the step of crystallization comprises: i) dissolution of compound (I) in a water-miscible solvent, ii) addition of water to the mixture, followed by crystallization of compound (I) and cooling between 0° C. and 5° C., and iii) collecting the filtered compound (I) in high purity by filtration.
 13. A process according to claim 12, wherein the water-miscible solvent is alkanol.
 14. A process according to claim 13, wherein the alkanol is methanol.
 15. A process according to claim 1, wherein the ratio of toluene and methyl ethyl ketone is 7:3 (w/w). 